Routine Use of Prophylactic Antibiotics during Laparoscopic Cholecystectomy Does Not Reduce the Risk of Surgical Site Infections

Abstract

Background:

Laparoscopic cholecystectomy (LC) is the gold standard for the treatment of symptomatic gallbladder stones. As infections are rare in uncomplicated LC, it is widely accepted that prophylactic antibiotics need not be administered, and guidelines do not support routine antibiotic prophylaxis during elective LC. However, routine antibiotic prophylaxis for elective LC is still popular in many clinical settings. We investigated this situation in our department.

Method:

This randomized double-blind controlled study included 570 patients who underwent LC between March 2007 and February 2010. The exclusion criteria were antibiotic intake before surgery, steroid treatment, and the presence of pancreatitis, cholangitis, obstructive jaundice, cephalosporin allergy, or pregnancy. The patients were randomized into three groups. Group 1 (n = 193) received physiologic saline as placebo, Group 2 (n = 191) received a first-generation cephalosporin (cefazolin; 1 g), and Group 3 (n = 186) received a second-generation cephalosporin (cefuroksim aksetil; 750 mg). Bile and epigastric and umbilical port tissue samples were harvested for culture. All patients were observed until the end of the fourth week after surgery. Patient age, sex, weight, American Society of Anesthesiologists (ASA) score, diabetes mellitus, smoking history, history of biliary colic in the past month, length of the hospital stay before the operation, operational findings (acute or chronic cholecystitis), operation duration, use of drainage, type of prophylaxis administered if any, culture results, surgical site infection (SSI) development, and time to SSI development along with associated treatments were evaluated.

Results:

There was no statistically significant difference between the groups with respect to any of the demographic and clinical features analyzed in this study. The SSI rate was 1.2% in total, and in Groups 1, 2, and 3, it was 1.5%, 1.04%, and 1.07%, respectively. There was no statistical difference regarding SSI among the groups (p = 1.00). Superficial SSI was observed in all groups, and in all patients, the site of infection was the entrance to the epigastric port through which the gallbladder had been removed.

Conclusions:

Surgical site infection is rare after LC, and antibiotic prophylaxis does not appear to affect the outcome significantly. Moreover, factors such as positive bile cultures, history of biliary attack, ASA score, diabetes, obesity, and smoking do not have any effect on SSI development. Thus, we conclude that antibiotic prophylaxis is not needed for elective LC.

Laparoscopic cholecystectomy (LC) is the gold standard for the treatment of symptomatic gallbladder stones. Compared with open cholecystectomy, laparoscopic surgery offers several significant advantages, including reduced trauma, a smaller incision, a shorter hospital stay, less risk of post-operative infections, and faster return to full activity. With 70,000 LCs performed every year in England, it can be considered rightly to be one of the most commonly performed surgical procedures [1]. However, surgical site infection (SSI) that may arise after an LC procedure negates the advantages offered by this technique. Therefore, it is imperative to take precautions for preventing SSIs. As infections are rare in uncomplicated LCs, it is widely accepted that prophylactic antibiotics need not be administered [2,3]; and hence, current guidelines do not recommend routine antibiotic prophylaxis for an elective LC [4,5]. A Cochrane meta-analysis was inconclusive with regard to the utility of antibiotic prophylaxis in reducing SSIs after LC [6]. However, because of possible bile contamination and gallbladder perforation during the dissection, the practice of antibiotic prophylaxis during elective LC differs from center to center, and many surgeons still prefer to use prophylactic antibiotics [7 –11].

In this study, we investigated the efficacy of prophylactic antibiotics against SSI in patients undergoing LC at our center. Our primary aim was to use the data thus generated for the creation of an evidential base for the standardization of surgical practice.

Patients and Methods

The current study was a double-blind, randomized, controlled trial aimed at investigating the effect of prophylactic antibiotic usage in patients undergoing LC for biliary stones (ethics committee approval number 2007–6/1; 3/27/2007).

All patients undergoing LC for cholelithiasis at Uludag University Faculty of Medicine, Department of General Surgery between April 1, 2007, and March 31, 2010, were included in the study. Patients who were pregnant; patients using an antibiotic within one week before the operation; those who presented with regular steroid use, cephalosporin allergy, obstructive jaundice, cholangitis, or pancreatitis; and those who had to be converted to open surgery during LC were excluded from the analysis.

After providing signed informed consent, the patients were divided into three groups: Group 1: placebo (saline)(n = 193); Group 2: first-generation cephalosporin (cephazoline 1 g)(191); and Group 3: second-generation cephalosporin (cefuroxim axetil 750 mg)(n = 186). The patients were randomized using a computer-generated random number pre-operatively. Administration of drug/placebo to each patient was chosen randomly and recorded by the clinic head nurse. Test materials coded with appropriate tags were transported in 10-mL syringes to the operating room and administered during induction anesthesia. Anesthesiologists, surgeons, and patients were blinded to the content of the syringes. Medication was administered only once and was not continued post-operatively. Gallbladders of all patients were removed routinely using the epigastric port and jaws. In case of perforation, we use an endobag via the epigastric port. Bile samples from the gallbladder and tissue samples from the epigastric and umbilical incision sites were cultured. After removal of the stitches, all patients were followed up twice for SSI during the third and fourth weeks post-operatively.

Age, sex, weight (>20% over ideal weight being considered a risk factor), American Society of Anesthesiologists (ASA) score, diabetes mellitus, smoking history, biliary colic in the past month, length of the hospital stay before the operation, operational findings (acute or chronic cholecystitis), operation duration (<1 h, 1–2 h, and >2 h), use of drainage, type of prophylaxis administered if any, culture results, SSI development, and time to SSI development along with associated treatments were evaluated. The groups were comparable with respect to their demographic and clinical features, culture results, and SSI. Data were analyzed with SPSS statistical software using the Pearson and χ² tests. A p value <0.05 was considered statistically significant.

Results

A total of 611 patients were enrolled, of which 41 were removed from the analysis according to the exclusion criteria (Fig. 1). All of the remaining 570 patients were discharged on post-operative day 1.

FIG. 1.

Removal of patients for noncompliance with eligibility criteria.

The demographic and clinical features of the groups are presented in Table 1. Of the patients, 71.5% were women, and the ratio of women to men did not show any statistically significant difference between the groups. The mean age of the groups also was similar (51, 53, and 54 y in Groups 1, 2, and 3, respectively). Although the number of patients of advanced age (>60 y) was higher in one of the prophylaxis groups, the difference was not statistically significant (p = 0.4). The number of patients who were 20% above their ideal weight was similar in the three groups. Although patients with an ASA score of 3 were more common in group 3 than in groups 1 and 2 (7.7%, 7.3%, and 11.3% in groups 1, 2, and 3, respectively), this difference was not statistically significant (p = 0.8). Among the patients, 11% in Group 1 had diabetes mellitus vs. 16% and 15% in Groups 2 and 3, respectively. History of smoking and the length of the pre-operative hospital stay also were similar in the three groups. The percentage of patients with an operation time <1 h was 93.7 in Group 1 and 95.8 and 95.1 in Groups 2 and 3, respectively. We placed drains in 43 patients. Nine of them had gallbladder perforation, 29 of them had bleeding from the gallbladder bed, one of them had cirrhosis, and four of them underwent intra-operative cholangiography. We placed drains in the patients having cholangiography because of the risk of bile leakage. There was no statistically significant difference among the groups with respect to any of these demographic or clinical features.

Table 1.

Clinical and Demographic Features of Patients According to Group ^a

	Group 1 (n = 193)	Group 2 (n = 191)	Group 3 (n = 186)
Sex (M/F)	48/145	52/139	62/124
Mean age (y)(min–max)	51 (17–84)	53 (25–82)	54 (22–89)
>60 years (%)	52 (26)	58 (30)	61 (32)
≥20% over ideal weight	127	130	123
Smoking history	35	42	44
Diabetes mellitus	22	32	29
American Society of Anesthesiologists score (1/2/3)	139/39/15	124/53/14	112/53/21
Pre-operative hospital stay (d)(min–max)	0.95 (0–4)	0.92 (0–3)	0.92 (0–3)
Biliary colic in the past month	73	71	69
Peri-operative findings of AC	5	4	3
Operation duration (<1 h/1–2 h/≥2 h)	181/12/ 0	183/8/0	177/9/0
Use of drainage	14	16	12

There was no statistical difference between the groups in any of the comparisons.

Bile culture results are presented in Table 2. The results were positive in 20.8% of the patients. This percentage was similar in all groups (20.2%, 20.9%, and 21.5%, respectively). The most common micro-organisms isolated were Escherichia coli in Groups 1 and 2 and Enterococcus in Group 3; however, this difference was not statistically significant (p = 0.37).

Table 2.

Distribution of Identified Micro-Organisms in Patients with Positive Bile Cultures

	Group 1 (n = 39)	Group 2 (n = 40)	Group 3 (n = 40)
Escherichia coli	17	15	11
Enterococcus	13	12	21
Staphylococcus	6	11	5
Enterobacter aerogenes	–	–	1
E. coli + Enterococcus	2	1	–
Streptococcus	–	1	–
Candida	–	–	1
Aeromonas	–	–	1
Bacillus	1	–	–

Three of the five Group 1 patients who presented with gallbladder wall edema and extensive inflammation at the dissection site intra-operatively did not have any growth in the bile cultures in spite of not having any pre-operative laboratory or clinical examination findings. One patient with a positive culture demonstrated growth of both E. coli and Enterococcus faecalis, whereas the other patient was positive only for Enterococcus faecium (Table 2). None of these patients developed SSI. Although four patients in Group 2 had acute cholecystitis and received cephazolin for prophylaxis, these patients did not have any growth in bile cultures, and none developed SSI. Three patients in Group 3 had acute cholecystitis, but the bile cultures were negative, and no SSI was detected post-operatively. All patients who developed peri-operative acute cholecystitis had had acute cholecystitis within the past month and had received medical treatment for it.

A comparative account of the micro-organisms isolated in the bile and port cultures is given in Table 3. Among the 19 cases from Group 1 that were positive for gram-negative micro-organisms in the bile, no gram-negative bacteria were isolated from the epigastric port of 16 (87.5%) and umbilical port of 17 (89.4%) of the patients. Similar percentage calculations for epigastric and umbilical ports for Groups 2 and 3 were 75% and 81.2% and 76.9% and 84.6%, respectively.

Table 3.

Distributions of Micro-Organisms within Groups According to Bile and Tissue Cultures

Port cultures	Epigastric port cultures													Umbilical port cultures
Bile cultures	Staphylococcus	Escherichia coli	Enterococcus	Escherichia coli + Enterococcus	Enterobacter	Streptococcus	Klebsiella	Acinetobacter	Candida	Corynebacterium	Bacillus	Aeromonas	Negative	Staphylococcus	Escherichia coli	Enterococcus	Escherichia coli +Enterococcus	Enterobacter	Candida	Bacillus	Providencia	Dermabacter	Negative
Group 1
Staphylococcus	1	–	–	–	–	–	–	–	–	–	–	–	5	4	–	–		–	–	–	–	–	2
Escherichia coli	13	1	–	–	–	–	–	–	–	–	–	–	3	14	1	–		–	–	–	–	–	2
Enterococcus	5	–	1	–	–	–	–	–	–	–	–	–	7	6	–	2		–	–	–	–	–	5
E. coli+ Enterococcus	–	–	-	2	–	–	–	–	–	–	–	–	–	1	1	–		–	–	–	–	–	–
Bacillus	1	–	–	–	–	–	–	–	–	–	–	–	–	–	–	–		–	–	–	–	–	1
Negative	28^a	1	1	–	–	–	–	–	–	1	1	–	122	24^a	–	–		–	1	–	–	1	128
Group 2
Staphylococcus	7	–	–	–	–	–	–	–	–	–	–	–	4	8	–	–		–	–	–	–	–	3
E. coli	8	3	–	–	–	–	–	–	–	–	–	–	4	8	2	–		–	–	–	–	–	5
Enterococcus	5	–	–	–	–	–	–	–	–	–	–	–	7	6		2		–	–	–	–	–	4
E. coli+ Enterococcus	–	–	–	1	–	–	–	–	–	–	–	–	–	–	1	–		–	–	–	–	–	–
Streptococcus	–	–	–	–	–	1	–	–	–	–	–	–	–	1	–	–		–	–	–	–	–	–
Negative	25^b	1	–	–	–	1	–	1	–	–	–	–	123	32^b	1	–		–	–	–	1	–	117
Group 3
Staphylococcus	5	–	–	–	–	–	–	–	–	–	–	–	–	3	–	–		–	–	–	–	–	2
E. coli	4	1	–	–	–	–	–	–	–	–	–	–	6	4	1	–		–	–	–	–	–	6
Enterococcus	12	–	2	–	–	–	–	–	–	–	–	–	7	13	–	2		–	–	–	–	–	6
E. coli+ Enterococcus	–	–	–	–	–	–	–	–	–	–	–	–	–	–	–	–		–	–	–	–	–	–
Enterobacter	–	–	–	–	1	–	–	–	–	–	–	–	–	–	–	–		1	–	–	–	–	–
Candida	-	–	–	–	–	–	–	–	1	–	–	–	–	–	–	–		–	–	–	–	–	1
Aeromonas	–	–	–	–	–	–	–	–	–	–	–	1	–	–	–	–		–	–	–	–	–	1
Negative	33 ^a	1	1	–	–	5	1	–	–	–	–	–	105	27^c	1	–		–	–	1	–	–	117

Staphylococcus epidermidis was isolated from the epigastric region in 13 patients and from the umbilical region in 11 patients.

Staphylococcus epidermis was isolated from the epigastric region in 11 patients and from the umbilical region in 11 patients.

Staphylococcus epidermidis was isolated from the epigastric region in 223 patients and from the umbilical region in 20 patients.

It is noteworthy that staphylococci were the micro-organisms most commonly isolated in the port cultures. Although only 22 cases of the 119 positive bile cultures (18.4%) yielded staphylococci, this percentage increased to 86.6% in the port cultures. A total of 344 positive port cultures were identified in the series (30.1% of 1,140 culture samples), and staphylococci were identified in 298 of these samples (86.6%). When individual groups were analyzed, in epigastric port samples, the positivity rate for Staphylococcus was 85.7%, 90%, and 79.4% in Groups 1, 2, and 3, respectively, whereas the positivity rate was 89%, 88.7%, and 88.6%, respectively, in the umbilical port samples. In short, the values were similar in all groups, and antibiotic prophylaxis did not appear to affect the results.

In Group 1, 10 of the 54 patients who had gram-positive bacteria in the epigastric port cultures also had gram-positive bacteria in the bile cultures. However, only three of 19 patients having gram-negative bacteria in their bile cultures also had gram-negative bacteria in the epigastric port cultures. Curiously, although cultures were negative for three samples, the remaining 15 samples (78.9%) yielded gram-positive bacteria instead. In Group 2, four of the 16 patients who had gram-negative bacteria in their bile cultures also demonstrated gram-negative bacteria in the epigastric port cultures, whereas nine were positive for gram-positive bacteria instead. In Group 3, 13 of the 40 patients who presented with positive bile cultures had gram-negative organisms, whereas only three (23%) were positive for gram-negative bacteria in the epigastric port cultures.

Seven patients (1.2%) developed SSI (Table 4). The SSI rates were 1.5%, 1.04%, and 1.07% for Groups 1, 2, and 3, respectively, with no statistical difference (p = 1.00). Superficial SSI was observed in all groups; and in all patients, the site of infection was the entrance of the epigastric port through which the gallbladder had been removed. An SSI was detected during the out-patient followups between the third and seventh post-operative days. If a patient did not have an SSI at these visits, they did not develop SSI later. All SSIs were managed with limited incision debridement and daily site dressing.

Table 4.

Features of Patients Who Developed a Surgical Site Infection ^a

	Bile Culture	Epigastric-port Culture	Diabetes Mellitus	Smoking	Weight≥20% Ideal	ASA Score	Age (y)	Biliary Colic	Peri-operative Signs of Acute Cholecystitis
Group 1
Patient 1	Negative	Staphylococcus haemolyticus	–	–	–	1	<60	+	–
Patient 2	Negative	Negative	–	–	–	1	<60	–	–
Patient 3	Negative	Negative	–	+	–	1	>60	–	–
Group2
Patient 1	Escherichia coli + Enterococcus	Escherichia coli + Enterococcus	+	–	–	3	>60	–	–
Patient 2	S. epidermidis	S. haemolyticus	–	+	–	1	<60	+	–
Group 3
Patient 1	Enterobacter aerogenes	E. cloacae	–	+	–	2	>60	+	–
Patient 2	Enterococcus	S. epidermidis	–	–	+	2	>60	+	–

Duration of operation was <1 h for all patients. All patients were treated with debridement and dressing.

ASA = American Society of Anesthesiologists.

Backward-stepwise conditional logistic regression analysis was found significant when including positive bile culture, positive port-site culture, and perforation of the gallbladder as risk factors (p = 0.026). The last model showed the epigastric port culture variable to be significant (p = 0.037). Specifically, the SSI risk was 5.779 times higher in port culture-positive patients than in those with negative cultures.

None of the 39 patients in Group 1 with a positive bile culture developed an SSI. Among the three patients who did develop SSIs, only one was positive for S. haemolyticus in the epigastric port culture, whereas port-culture results for the other two patients were negative. In other words, only one (1.78%) of the 56 patients with positive epigastric-port cultures developed SSI in this group. None of the patients with SSI had a history of use of drainage tubes. Only one of the three patients with SSI had a history of biliary colic in the past month, whereas another patient had a history of smoking. In Group 2, only two of the 40 patients with positive bile cultures developed an SSI. One of the two patients with SSI was positive for E. coli and Enterococcus in both bile and epigastric-port cultures. The other patient was positive for gram-positive bacteria in both the bile and the epigastric-port cultures. In this group, none of the patients with an SSI had a drainage tube. One patient had a history of smoking and biliary colic, whereas the other patient was diabetic with an ASA score of 3. In Group 3, only two patients (2.6%) of the 68 with positive epigastric-port cultures developed an SSI. One of the patients was positive for Enterobacter in both bile and port cultures, whereas the other was positive for Enterococcus in the bile culture and Staphylococcus in the epigastric-port culture. The patients who developed SSI in this group did not have a drainage tube. Both patients had a history of biliary colic and an ASA score of 2. In addition, one of the patients suffered from obesity, and the other had a smoking history.

Discussion

Earlier investigators reported that the frequency of SSI after LC ranged from 0.4% to 6.3% [7,12 –15]. Although antibiotic prophylaxis is recommended for reducing infectious complications in open cholecystectomy, which is a clean-contaminated operation, this is not the case with LC [15 –17,21]. Many prospective studies have demonstrated that because the risk of infection is low in LC, antibiotic prophylaxis is not needed, as it does not reduce the likelihood of SSI or other infectious complications [3,20].

Despite this evidential base, many surgeons still use antibiotic prophylaxis during LC, which is one of the most common operations in surgical practice. The rationale is that the infected bile may spread if there is a gallbladder perforation. The rate of bile culture positivity is reported to range from 10%–42.5% in patients with bile stones [7,12,13,18,19]. In our study, we quantified this figure at 20.8%. The micro-organisms most commonly isolated are Escherichia coli, Enterobacter, and Klebsiella. The frequency of gallbladder perforation during LC is between 2% and 25% [20 –24]; therefore, contamination as a result of perforation is proposed as a risk factor for SSI. Shindholimath et al. reported that infected bile is an important factor in SSI development after elective LC and that prophylactic antibiotics decrease the frequency of incision infections [7]. However, the association between positive bile cultures and SSI is controversial, and many studies have failed to shed light on the hypothetical connection between SSI and positive bile cultures, gallbladder perforation, or spillage of bile stones into the abdomen [2,13,25]. In a meta-analysis, Yan et al. did not observe any statistically significant difference between the development of superficial or deep SSIs and positive bile cultures and the groups that did or did not receive antibiotics [2]. In a study by Koc et al., the rate of bile spillage was approximately 19.5%, and there was no correlation between bile contamination and incision infection [13]. Umbilical flora and bile could not be identified as a source of post-operative SSI in the study conducted by Hamzaoğlu et al. [26]. Similarly, we did not detect a correlation between positive bile cultures and SSI. In addition, independent of the use of prophylactic antibiotics, the detection rate of gram-negative bacteria in bile cultures was 30% in all groups and 8.2% in port cultures alone, whereas 91.7% of port cultures were positive for gram-positive bacteria. The fact that staphylococci were detected in a majority of positive epigastric- and umbilical-port cultures is suggestive of contamination.

Consistent with the published data, the SSI rate in our study was approximately 1.2%, and this rate did not show any statistically significant difference among the groups according to antibiotic use (1.5%, 1.04%, and 1.07% in Groups 1, 2, and 3, respectively; p = 1.00). Bile cultures were positive in 119 (20.8%) of the 570 patients included in the study. In two of the three patients in Group 1 who developed SSI, bile and port cultures were negative, whereas in the third patient, bile cultures were negative, but the epigastric-port culture exhibited growth of S. epidermidis. In Groups 2 and 3, there was growth in bile and tissue cultures obtained during the operations on both of the patients who developed SSI. One patient in Group 2 had E. coli and Enterococcus in both cultures, whereas the other patient had only Staphylococcus; in Group 3, one patient was positive for Enterococcus in both bile and port cultures, whereas the other had Enterococcus and Staphylococcus. In short, bile culture results and the cause of SSI correlated in only three of seven patients. These data demonstrate that there is no direct association between the micro-organism isolated from bile cultures and that causing SSI.

Studies indicate that the history of acute biliary colic within one month prior to the operation, ASA score, age >60, and diabetes mellitus are risk factors for the development of SSI after LC [13,18,21]. We did not detect any association between diabetes mellitus, obesity, or smoking and SSI development. Analyzing the ASA score, none of the 375 patients with ASA 1 developed SSI, only two of the 145 patients with ASA 2, and one of the 50 patients with ASA 3 developed SSI. Although there was an increase in SSI development with increasing grade, this difference was not statistically significant (p = 0.11), and it is to be noted that all the patients who developed an SSI had received prophylaxis.

When SSI development was analyzed along with the effect of advanced age (>60) and the choice of prophylaxis, 30.1% of the patients were older than 60, and 2.3% of these patients developed SSI (1.9%, 1.7%, and 3.2% in Groups 1, 2, and 3, respectively), whereas only 0.7% of the patients aged ≤60 y developed SSI (1.4%, 0.7%, and 0 in groups 1, 2 and 3, respectively). Although this difference is not statistically significant (p = 0.2), the increase in SSI rates in patients >60 is noteworthy. Prophylaxis did not affect this increase. Our results parallel those reported by Ruangsin et al. involving 299 patients wherein advanced age was not found to be a risk factor for SSI even though 57.1% of the patients who developed SSI were older than 60 y [27].

In the series published by Darkahi et al., in which the authors analyzed 1,171 cases, patients were first divided into high-risk and low-risk groups followed by further subdivision into groups that did or did not receive antibiotics. In the multivariable analysis, antibiotics had no efficacy in preventing infections [25]. On the other hand, the randomized controlled study by Koc et al. with 112 patients showed that age, diabetes mellitus, and a history of bile stone attack within one month before the operation were independent risk factors for infectious complications; the same study also revealed that patients with septic complications had negative bile cultures and that there was no correlation between complications and bile flora [13].

In our study, a total of 213 cases (37.3%) had had a biliary colic attack in the month preceding the operation. Four of these patients (1.9%) developed SSI, whereas three of them had positive bile cultures. In the 357 patients who presented without a history of biliary colic, this is equivalent to a rate of 0.8%; but this difference was not statistically significant (p = 0.43). This rate was not affected by prophylaxis, and there was no significant association observed between biliary colic attack and SSI in any of the groups (p = 0.5). On the other hand, 13 patients who had signs of acute cholecystitis intra-operatively, despite having normal pre-operative clinical and laboratory findings, were distributed similarly in all the groups, but none of these patients developed SSI. Only two of the five patients with acute cholecystitis in Group 1, those who did not receive antibiotic prophylaxis, were positive for gram-negative bacteria in the bile cultures, whereas similar culture tests were negative for patients in the groups that received prophylaxis. It is remarkable that only two of 13 cases had positive bile cultures and that none of these patients, including those who did not receive prophylaxis, developed an SSI. As revealed in this study, we propose that considering patients with a history of acute cholecystitis who are clinically cured in the same group as those with chronic cholecystitis with regard to SSI prophylaxis is a better approach.

In conclusion, SSI is rare after LC, and antibiotic prophylaxis does not appear to affect the outcome significantly. Moreover, additional factors such as positive bile cultures, history of biliary stone attack, ASA score, diabetes mellitus, obesity, and smoking likewise do not have any effect on SSI development. Thus, we conclude that antibiotic prophylaxis is not needed during elective LC.

Footnotes

Acknowledgment

Presented at the 16th Annual Meeting of the European Society of Surgery (ESS), Istanbul, Turkey, November 22, 2012.

Author Disclosure Statement

No competing financial interests exist for any of the authors.

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